Abstract

The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%-75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction.

The strength of cortico-STN transmission decreased following chemogenetic activation of D2-SPNs in dopamine-intact mice

(A, B) Expression of rM3Ds-mCherry in D2-SPNs (A, red arrows) and their axon terminal fields in the GPe (B) in the adora2A-rM3Ds-mCherry mouse. Expression was absent in putative D1-SPNs (A; white arrows) and their axon terminal fields in the SNr (C). (B, C) Expression was also absent in GPe (B; white arrows) and SNr (C; white arrows) neurons. Immunohistochemistry for NeuN (white) was used as a neuronal marker in A–C. (D–F) Chemogenetic activation of rM3Ds in D2-SPNs through subcutaneous (SC) injection of CNO (1 mg/kg) led to inhibition of open field motor activity relative to vehicle injection. (D) Representative examples of open field activity before and after first injection. (E, F) Population data confirming that CNO injection reduced movement traveled in the open field (E, left and right box plots for vehicle and CNO represent movement prior to and following first injection, respectively; F, movement following injection of vehicle or CNO over 3 consecutive days). (G) Simultaneous recordings of the electroencephalogram (EEG) band pass filtered at 0.5–1.5 Hz and 10–100 Hz, and GPe unit activity in a urethane-anesthetized adora2A-rM3Ds-mCherry mouse prior to (control), and 30–45 mins following the SC administration of CNO (1 mg/kg). The rate of GPe unit activity during periods of robust cortical slow-wave activity decreased following the injection of CNO both in each example neuron (G) and across the population sample (H). (I–K) the frequency (I, J) (but not the amplitude; I, K) of mIPSCs in GPe neurons was greater in brain slices treated with CNO (10 μM) ex vivo versus untreated control slices (I, representative examples; J, K, population data). (L–P) Subcutaneous injection of CNO every 12 hours for 2–3 days led to a reduction in the density of vGluT1 expressing cortico-STN axon terminals (L–N) and to a reduction in the amplitude of optogenetically stimulated (blue arrow) cortico-STN transmission (O, P) relative to vehicle-injected control mice (L, M, representative micrographs; N, population data; O, representative traces; P, population data). Blue arrow, optogenetic stimulation; *, p < 0.05. ns, not significant. See also .